{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T08:06:52Z","timestamp":1766390812077,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,1,21]],"date-time":"2023-01-21T00:00:00Z","timestamp":1674259200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Grant-in-Aid for Clinical Research from the National Hospital Organization","award":["H28-NHO (Shinkei)-01","J7201"],"award-info":[{"award-number":["H28-NHO (Shinkei)-01","J7201"]}]},{"name":"pharmaceutical Research grants from Doshisha Women\u2019s College of Liberal Arts","award":["H28-NHO (Shinkei)-01","J7201"],"award-info":[{"award-number":["H28-NHO (Shinkei)-01","J7201"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cardiomyopathy is the leading cause of death in patients with muscular dystrophy (MD). Tranilast, a widely used anti-allergic drug, has displayed inhibitory activity against the transient receptor potential cation channel subfamily V member 2 and improved cardiac function in MD patients. To identify urinary biomarkers that assess improved cardiac function after tranilast administration, we performed a urinary metabolomic study focused on oxidative fatty acids. Accompanying the clinical trial of tranilast, urine specimens were collected over 24 weeks from MD patients with advanced heart failure. Urinary levels of tetranor-PGDM (tetranor-prostaglandin D metabolite), a metabolite of prostaglandin D2, significantly decreased 12 weeks after tranilast administration and were correlated with BNP. These results suggest that prostaglandin-mediated inflammation, which increases with the pathological progression of heart failure in MD patients, was attenuated. Urinary prostaglandin E3 (PGE3) levels significantly increased 4 weeks after tranilast administration. There were positive correlations between the urinary levels of PGE3 and 8-hydroxy-2\u2032-deoxyguanosine, an oxidative stress marker. High PGE3 levels may have a protective effect against cardiomyopathy in MD patients with high oxidative stress. Although further validation studies are necessary, urinary tetranor-PGDM and PGE3 levels may help the current understanding of the extent of advanced heart failure in patients with MD after tranilast administration.<\/jats:p>","DOI":"10.3390\/ijms24032167","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T02:27:45Z","timestamp":1674440865000},"page":"2167","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Impact of the TRPV2 Inhibitor on Advanced Heart Failure in Patients with Muscular Dystrophy: Exploratory Study of Biomarkers Related to the Efficacy of Tranilast"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7215-8726","authenticated-orcid":false,"given":"Chisato","family":"Takahashi","sequence":"first","affiliation":[{"name":"Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Doshisha Women\u2019s College of Liberal Arts, Kyotanabe 610-0395, Kyoto, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mariko","family":"Oishi","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Doshisha Women\u2019s College of Liberal Arts, Kyotanabe 610-0395, Kyoto, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuko","family":"Iwata","sequence":"additional","affiliation":[{"name":"Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, 6-1 Kishibe-Shimmachi, Suita 564-8565, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4857-4137","authenticated-orcid":false,"given":"Keiko","family":"Maekawa","sequence":"additional","affiliation":[{"name":"Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Doshisha Women\u2019s College of Liberal Arts, Kyotanabe 610-0395, Kyoto, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6241-3626","authenticated-orcid":false,"given":"Tsuyoshi","family":"Matsumura","sequence":"additional","affiliation":[{"name":"Department of Neurology, National Hospital Organization Osaka Toneyama Medical Center, 5-1-1 Toneyama, Toyonaka 560-8551, Osaka, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"957","DOI":"10.1083\/jcb.200301101","article-title":"A Novel Mechanism of Myocyte Degeneration Involving the Ca2+-Permeable Growth Factor-Regulated Channel","volume":"161","author":"Iwata","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1093\/cvr\/cvt163","article-title":"Blockade of Sarcolemmal TRPV2 Accumulation Inhibits Progression of Dilated Cardiomyopathy","volume":"99","author":"Iwata","year":"2013","journal-title":"Cardiovasc. Res."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Iwata, Y., and Matsumura, T. (2019). Blockade of Trpv2 Is a Novel Therapy for Cardiomyopathy in Muscular Dystrophy. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20163844"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1093\/hmg\/ddn408","article-title":"Dominant-Negative Inhibition of Ca2+ Influx via TRPV2 Ameliorates Muscular Dystrophy in Animal Models","volume":"18","author":"Iwata","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3600","DOI":"10.1016\/j.febslet.2009.10.033","article-title":"Essential Role of TRPV2 Ion Channel in the Sensitivity of Dystrophic Muscle to Eccentric Contractions","volume":"583","author":"Zanou","year":"2009","journal-title":"FEBS Lett."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.bcp.2005.05.034","article-title":"Protective Effects of Ca2+ Handling Drugs against Abnormal Ca2+ Homeostasis and Cell Damage in Myopathic Skeletal Muscle Cells","volume":"70","author":"Iwata","year":"2005","journal-title":"Biochem. Pharmacol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"743","DOI":"10.5692\/clinicalneurol.51.743","article-title":"A longitudinal cause-of-death analysis of patients with Duchenne muscular dystrophy","volume":"51","author":"Matsumura","year":"2011","journal-title":"Rinsho Shinkeigaku"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"8823","DOI":"10.3390\/molecules20058823","article-title":"Current Understanding of Molecular Pathology and Treatment of Cardiomyopathy in Duchenne Muscular Dystrophy","volume":"20","author":"Betts","year":"2015","journal-title":"Molecules"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"311","DOI":"10.2169\/internalmedicine.8651-16","article-title":"A Pilot Study of Tranilast for Cardiomyopathy of Muscular Dystrophy","volume":"57","author":"Matsumura","year":"2018","journal-title":"Intern. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"121","DOI":"10.2739\/kurumemedj.MS662006","article-title":"Study Protocol for a Multicenter, Open-Label, Single-Arm Study of Tranilast for Cardiomyopathy of Muscular Dystrophy","volume":"66","author":"Matsumura","year":"2019","journal-title":"Kurume Med. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/s13023-022-02352-3","article-title":"Tranilast for Advanced Heart Failure in Patients with Muscular Dystrophy: A Single-Arm, Open-Label, Multicenter Study","volume":"17","author":"Matsumura","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.cca.2013.03.031","article-title":"A Prostaglandin D2 Metabolite Is Elevated in the Urine of Duchenne Muscular Dystrophy Patients and Increases Further from 8 Years Old","volume":"423","author":"Nakagawa","year":"2013","journal-title":"Clin. Chim. Acta."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.braindev.2018.06.012","article-title":"Urinary Prostaglandin Metabolites as Duchenne Muscular Dystrophy Progression Markers","volume":"40","author":"Takeshita","year":"2018","journal-title":"Brain Dev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s12970-020-00391-4","article-title":"Effect of 8-Week n-3 Fatty-Acid Supplementation on Oxidative Stress and Inflammation in Middle- and Long-Distance Running Athletes: A Pilot Study","volume":"17","author":"Buonocore","year":"2020","journal-title":"J. Int. Soc. Sports Nutr."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.yjmcc.2013.02.008","article-title":"Global Metabolomic Analysis of Heart Tissue in a Hamster Model for Dilated Cardiomyopathy","volume":"59","author":"Maekawa","year":"2013","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1074\/jbc.M706839200","article-title":"Tetranor PGDM, an Abundant Urinary Metabolite Reflects Biosynthesis of Prostaglandin D2 in Mice and Humans","volume":"283","author":"Song","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s00401-002-0567-z","article-title":"Induction of Hematopoietic Prostaglandin D Synthase in Hyalinated Necrotic Muscle Fibers: Its Implication in Grouped Necrosis","volume":"104","author":"Okinaga","year":"2002","journal-title":"Acta Neuropathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/S0021-5198(19)32428-X","article-title":"Inhibitory Action of Tranilast, an Anti-Allergic Drug, on the Release of Cytokines and PGE2 from Human Monocytes-Macrophages","volume":"60","author":"Suzawa","year":"1992","journal-title":"Jpn. J. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1016\/S0006-2952(97)00187-1","article-title":"Suppressive Effects of Tranilast on the Expression of Inducible Cyclooxygenase (COX2) in Interleukin-1beta-Stimulated Fibroblasts","volume":"53","author":"Inoue","year":"1997","journal-title":"Biochem. Pharmacol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.bcp.2003.08.028","article-title":"COX-2-Mediated PGD2 Synthesis Regulates Phosphatidylcholine Biosynthesis in Rat Renal Papillary Tissue","volume":"67","author":"Kraemer","year":"2004","journal-title":"Biochem. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2673","DOI":"10.1016\/0006-2952(89)90553-4","article-title":"Inhibitory Effect of Tranilast on Prostaglandin D Synthetase","volume":"38","author":"Ikai","year":"1989","journal-title":"Biochem. Pharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s00418-012-1056-7","article-title":"Cyclooxygenase-2 Expression in Skeletal Muscle of Knockout Mice Suffering Duchenne Muscular Dystrophy","volume":"139","author":"Quintana","year":"2013","journal-title":"Histochem. Cell Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/s41374-019-0363-1","article-title":"Production of TRPV2-Targeting Functional Antibody Ameliorating Dilated Cardiomyopathy and Muscular Dystrophy in Animal Models","volume":"100","author":"Iwata","year":"2020","journal-title":"Lab. Investig."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8836","DOI":"10.7150\/thno.63396","article-title":"Role of Prostaglandin E2 in Tissue Repair and Regeneration","volume":"11","author":"Cheng","year":"2021","journal-title":"Theranostics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"495","DOI":"10.1080\/07315724.2002.10719248","article-title":"Omega-3 Fatty Acids in Inflammation and Autoimmune Diseases","volume":"21","author":"Simopoulos","year":"2002","journal-title":"J. Am. Coll. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1093\/cvr\/cvp169","article-title":"Omega-3 Polyunsaturated Fatty Acid Supplementation for the Treatment of Heart Failure: Mechanisms and Clinical Potential","volume":"84","author":"Duda","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.amjcard.2005.12.022","article-title":"Dietary Omega-3 Fatty Acid Intake and Cardiovascular Risk","volume":"98","author":"Psota","year":"2006","journal-title":"Am. J. Cardiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1054\/plef.2000.0226","article-title":"Beneficial Effect(s) of n-3 Fatty Acids in Cardiovascular Diseases: But, Why and How?","volume":"63","author":"Das","year":"2000","journal-title":"Prostaglandins Leukot. Essent. Fatty Acids"},{"key":"ref_29","first-page":"e20","article-title":"Fish Consumption, Fish Oil, Omega-3 Fatty Acids, and Cardiovascular Disease","volume":"23","author":"Harris","year":"2003","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1991S","DOI":"10.1093\/ajcn\/87.6.1991S","article-title":"Fish and N-3 Fatty Acids for the Prevention of Fatal Coronary Heart Disease and Sudden Cardiac Death","volume":"87","author":"Mozaffarian","year":"2008","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.canlet.2014.03.010","article-title":"Prostaglandin E3 Metabolism and Cancer","volume":"348","author":"Yang","year":"2014","journal-title":"Cancer Lett."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1593\/neo.10388","article-title":"Effect of Eicosapentaenoic Acid on E-Type Prostaglandin Synthesis and EP4 Receptor Signaling in Human Colorectal Cancer Cells","volume":"12","author":"Hawcroft","year":"2010","journal-title":"Neoplasia"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"22254","DOI":"10.1074\/jbc.M703169200","article-title":"Enzymes and Receptors of Prostaglandin Pathways with Arachidonic Acid-Derived versus Eicosapentaenoic Acid-Derived Substrates and Products","volume":"282","author":"Wada","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1080\/00365510260390019","article-title":"Evidence of Increased Oxidative Stress by Simple Measurements in Patients with Dilated Cardiomyopathy","volume":"62","author":"Topkaya","year":"2002","journal-title":"Scand. J. Clin. Lab. Investig."},{"key":"ref_35","first-page":"851","article-title":"The Relationship between Potency of Oxidative Stress and Severity of Dilated Cardiomyopathy","volume":"21","author":"Demirbag","year":"2005","journal-title":"Can. J. Cardiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.atherosclerosis.2010.12.013","article-title":"Effect of N-3 Fatty Acids and Statins on Oxidative Stress in Statin-Treated Hypercholestorelemic and Normocholesterolemic Women","volume":"217","author":"Carrepeiro","year":"2011","journal-title":"Atherosclerosis"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1053\/j.jrn.2010.01.002","article-title":"Effects of Omega-3 Polyunsaturated Fatty-Acid Supplementation on Redox Status in Chronic Renal Failure Patients with Dyslipidemia","volume":"20","author":"Bouzidi","year":"2010","journal-title":"J. Ren. Nutr."},{"key":"ref_38","first-page":"20","article-title":"Targeted Lipidomics of Oxylipins (Oxygenated Fatty Acids)","volume":"147","author":"Strassburg","year":"2015","journal-title":"Waters Appliction Note"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1007\/s00216-012-6226-x","article-title":"Quantitative Profiling of Oxylipins through Comprehensive LC-MS\/MS Analysis: Application in Cardiac Surgery","volume":"404","author":"Strassburg","year":"2012","journal-title":"Anal. Bioanal. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"102157","DOI":"10.1016\/j.plefa.2020.102157","article-title":"Evaluation of Cyclooxygenase Oxylipins as Potential Biomarker for Obesity-Associated Adipose Tissue Inflammation and Type 2 Diabetes Using Targeted Multiple Reaction Monitoring Mass Spectrometry","volume":"160","author":"Tans","year":"2020","journal-title":"Prostaglandins Leukot. Essent. Fat. Acids"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Okemoto, K., Maekawa, K., Tajima, Y., Tohkin, M., and Saito, Y. (2016). Cross-Classification of Human Urinary Lipidome by Sex, Age, and Body Mass Index. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0168188"},{"key":"ref_42","unstructured":"Shimadzu (2022, December 10). Comprehensive Monitoring Method for Analyzing 158 Lipid Mediator Species Using the Ultra-Fast LCMS-8050 Shimadzu Applications News. 2014, No.C102. Available online: https:\/\/www.shimadzu.com\/an\/literature\/lcms\/jpo114099.html."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2167\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:13:06Z","timestamp":1760119986000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2167"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,21]]},"references-count":42,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24032167"],"URL":"https:\/\/doi.org\/10.3390\/ijms24032167","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,1,21]]}}}